The Animal And Clinical Studies About Effects Of Rosiglitazone On Vascular Restenosis

Restenosis after percutaneous transluminal coronary angioplasty(PTCA) and stent impalntation remains the major problem that hampers the procedure′s efficacy, occurring in 20-30% of patients. Now, restenosis become a hindrance in the field of interventional cardiology. Although the application of drug-eluting stent has been shown to reduce restenosis rates after percutaneous coronary intervention(PCI) significantly, its long-term effects still need further observation. So people turned their attention to the medicine that can prevent restenosis. As we known, thrombosis, inflammation, and proliferation of vascular smooth muscular cells(VSMCs) should account for the formation of restenosis, so the medicine of anti-restenosis also works by the three channels.The thiazolidinediones are a class of pharmacological compounds with high affinity to peroxisome proliferator–activated receptors(PPARs). Studies in recent years have shown that these drugs can not only increase the sensitivity of insulin,but also inhibit the proliferation and immigration of VSMCs and inhibit the vascular inflammation. Up to now, the effects of thiazolidinediones to vascular endothelial function remain indefinite, and the results above-mentioned are mostly based on cell study in vitro or animal studies.Objective:To establish the model of vascular restenosis after PCI, then observe and study the vascular endothelial function, inflammatory reaction, VSMCs proliferation after application of rosiglitazone with animal reaserches and clinical studies.Methods:The partⅠ,Ⅱbelong to animal study. In partⅠ, the model of vascular restenosis established by balloon injury of rat carotid arteries was performed. Rats were killed at different time points after balloon injury. Sections of balloon injury were taken out and made specimens, then stained with HE and elastic fiber. Pathologic change of the arterial wall at different time after balloon injury was observed by microscopy, then the lumen area, thickness and area of intima and media at different time after balloon injury were measured by computer image analysis technology. In partⅡ, pathologic change of the arterial wall at different time after balloon injury was observed by microscopy with HE and elastic fiber staining after therapy of rosiglitazone. The immunohistochemical technique was used to study the proliferation rate of VSMCs and NF-κB expression of vessel wall cells. The TUNEL method was used to study apoptosis rate of VSMCs.The latter two parts belong to clinical study. Patients were divided into therapy group and control group according to whether rosiglitazone is taken or not. Venous blood samples were taken before and some moments in 1 month after implantation of stents. In partⅢwe observed the changes of levels of blood inflammatory factors after implantation of stents and investigated the effects of rosiglitazone on inflammatory factors. In partⅣwe observed the changes of levels of vascular endothelial active materials after implantation of stents and investigated the effects of rosiglitazone on vascular endothelial active materials.Results:PartⅠ1. Compared with normal rat carotid artery, at 7 days after injury the neointima formed. The proliferating of VSMCs was spotted on the surface of lumen. At 14 days after injury the neointima was continuously thickening and extracellular matrix was increasing. But the proliferation of VSMCs was decreasing. At 28 days after injury the neointima was continuously thickening and the vascular lumen became narrow seriously.2. Compared with normal rat carotid artery, at 7 days after injury the area of neointima increased significantly. At 14 to 28 days after injury, the area of the neointima was increasing continuously. But area of the media did not significantly change.PartⅡ1. After therapy of rosiglitazone, area of the neointima and lumen stenosis index decreased significantly.2. After therapy of rosiglitazone, VSMCs proliferation rates decreased significantly. VSMCs apoptosis rates increased significantly. And NF-κB expressions also decreased significantly.PartⅢ1. At 24 hours and 7 days after PCI the levels of MCP-1 and ICAM-1 of both therapy group and control group were significantly higher than the levels before PCI. There were significant difference between therapy group and control group in the levels of MCP-1 and ICAM-1 at 24 hours and 7 days after PCI. 2. At 24 hours, 7 days and 1 month after PCI, the levels of CRP of both therapy group and control group were significantly higher than the levels before PCI. There were significant difference between therapy group and control group about in the levels of CRP at 24 hours after PCI. At 24 hours and 7 days after PCI, the levels of IL-6 of therapy group and control group increased significantly, compared with the levels before PCI. There were significant difference between therapy group and control group in the levels of IL-6 at 24 hours and 7 days after PCI.PartⅣ1. At 24 hours and 7 days after PCI, the levels of NO, NOS and ET-1 of both therapy group and control group were significantly different from the levels before PCI. At 1 month after PCI the levels of NO and NOS of therapy group and control group were significantly different from the levels before PCI. There were significant difference between therapy group and control group in the levels of NO, NOS and ET-1 at 24 hours and 7 days after PCI. There were also significant difference between therapy group and control group in the levels of NO and NOS at 1 month after PCI.Conclusions:1. The model of vascular restenosis can be established by PTCA balloon injury of rat carotid arteries. This model can be applied to restenosis researches.2. After vascular endothelium is injuried, the migration and proliferation of VSMCs and the production of extracellular matrix can lead to neointimal hyperplasia. These procedures form an important pathologic pathogenesis of vascular restenosis.3. Rosiglitazone can produce a significant inhibition of neointimal hyperpalsia in rats carotid arteries after balloon dilation, by inibiting the proliferation of VSMCs and promoting the apoptosis of cells. And the low expression of NF-κB is involved in this procedure.4.The vascular inflammation after PCI in patients with coronary heart disease mainly happens at 7 days to 1 month after stent implantation. The inflammation results from mechanic stimuli, injury of endothelium, and implantation of stent and fades away gradually because of endothelium generation. Compared with control group, rosiglitazone can significantly decrease the levels of blood inflammatory factors and inhibit inflammation after PCI.5. The impaired function of endothelium after PCI in patients with coronary heart disease mainly happens at 1 month after stent implantation. Compared with control group, rosiglitazone can significantly improve function of endothelium and decrease the levels of NO,NOS, and increased the level of ET-1.